Bioavailability Studies of Acetaminophen and Nitrofurantoin

Transcription

1 ioavailability Studies of cetaminophen and Nitrofurantoin K. S. LERT. Ph.D... J. SEDMN. P. WILKINSON. 1. G. STOLL,* Ph.D.. W. J. MURRY.t M.D.. Ph.D.. and J. G. WGNER. Ph.D. nn rbor, Mkk. T HE effects of dosage form variables on therapeutic efficacy and/or bioavailability of drugs are well documented.m Usually, these effects will be manifest principally in differences in rate of absorption and/or differences in efficiency of absorption. Since a formulation which releases a drug slowly over an extended time could have the same bioavailability as a formulation with a more rapid rate of absorption, it is important to commsider both rate and extent of absorption as criteria for assessing therapeutic equivalency. Uwilt et al.2 mmoted differences imm blood and plasma levels of aeetaminophen after administering 1 Gm of drug as whole tablets (eight different manufacturers), as crushed tablets (one manufacturer), and as a tablet containing sorbitol. However, his comparisons were made at a single sampling time (45 minutes after administration). McGilveray et al.3 compared efficiencies and rates of absorption of eight Prom the College of Pharmacy and Upjohn Center for Clinical Pharmacology, University of Michigan, nn rbor, Mich. These studies were supported by a contract from the R. P. Scherer Corporation. * Present address: Clinical ioavailability Unit, The Upjohn Company, Kalamazoo, Mich. Present address: Department of nesthesiology, Duke University Medical Center, Durham, N.C. lots of tablets, one elixir, and an aqueous solution of acetaminophen in ten subjects each receiving 1-Gm doses weekly f or ten weeks. No differences in rate or extent of availability were noted among formnulations from either blood level or urinary excretion data after monitoring free drug as well as total levels. Mattok et al.4 observed the semmsitivitv of the bioavailability of mmitrofurantoin to changes in formulation of the drug. One liundred-milligrani doses of nitrofurantoin were administered to 30 subjects in the form of conmnmercially available tablets from one manufacturer. ioavailabilities based on urinary data were expressed as per cent of that obtained with a eormtrol suspension as well as the per cent of the innovator s product. n in vivo-in vitro comparison was attempted, but results indicated that the dissolution tests did not accurately reflect in vivo absorption. In a recent study, Horn and MiskeP demonstrated enhanced in vitro rates of dissolution for a series of chemically and pharmacologically different drugs when formulated in special soft gelatin capsules compared to commercially available tablets. Since in vitro dissolutiomi rate reflects the bioavailability potential of a drug in a dosage form, two human studies were undertakemi to compare plasma levels and urinary excretion of the drugs acetamino- 264 The Journal of Clinical Pharmacology

2 IOVILILITY OF CETMINOPHEN ND N1TROFURNTOIN Treatment I Schedules* Phase Study Subject no. Group I II cetaminophen 1, 2, 3, 4, 5, 1 6,7,8,9,10 2 Nitrofurantoin 1, 2, 3, 4, 5, 1 6,7,8,9,10 2 *The studies were separated by about 6 months; phases were separated by a 1-week period. For acetaminophen, treatment is the soft gelatin capsule (. P. Scherer Corp.), treatment is the commercial tablet (Tylenol, McNeil). For nitrofurantoin, treatment is the soft gelatin capsule (. P. Scherer Corp.), treatment is the commercial tablet (Puradantin, Eaton). phen ammd nitrofurantoin. Single oral doses given as commercially available tablets and as specially formulated soft gelatin capsules were used in these two studies. (Poloxamer 212 was the surfactant in the acetaminophen formulation, while Poloxamer 212 and Poloxamer 234, in a ratio of 4 to 1, were used as bases in the nitrofurantoin capsule.) Materials and Methods Ten healthy male volunteers chosen for each study were selected based upon criteria previously described.6 The studies were performed using a Latin-square crossover design with two groups of five subjects possessing similar average body weights. The study conditions were essentially as described previously,6 with the following modifications. cetaminophen. On the mornings acetamninophen was administered, each subject drank 6 fi oz of water within the first hour after arisimig and 6 fi oz of water when the medication was administered. On each phase of the two-way crossover, each subject took two 325-mg capsules (treatment ) or two 325-mg tablets (treatmemit ), swallowing the preparations intact. (Treatment was the soft gelatin capsule, R. P. Scherer Corp.; treatment was Tylenol tablets, McNeil Laboratories.) lood, 10 ml, was withdrawn from a forearm vein prior to dosing and at 10, 20, 30, 40, 60, 120, 240, 360, 480, and 720 minutes after dosing. Zero- to 24- hour urine specimens were also obtained and stored in plastic bottles containing 1 ml toluene. fter collection, the volume was measured and the urine was quickfrozen and kept in a frozen state until just prior to assay. Plasma and urine samples were assayed by the GLC procedure described by Kostenbauder.7 Nit rof urantoin. On the mornings nitrofurantoin was administered, each subject drank 6 fi oz of water at -2, -1, 0, + 1, + 2, ± 3, + 4, and + 5 hours, where 0 is the time of dosing. On each phase of the two-way study, each subject ingested one capsule (treatment ) or a tablet containing 100 mg nitrofurantion (treatment ). (Treatment was the soft gelatin capsule, R. P. Scherer Corp.; treatment here was Furadantin tablets, Eaton Laboratories.) lood, 10 ml, was withdrawn from a forearm vein prior to dosing and at 10, 20, 30, 40, 60, 120, and 240 minutes after May-June,

3 LERT ET L. II Summary of verage Plasma Concentrations and 24-Hour Urinary Excretion of cetaminophen in Ten Normal Subjects Following a Single 650-mg Oral Dose Significance C. V. verage plasma concentration level of difference (%) from (g/ml) between treatment residual Treatment Treatment averages from NOV mean square Time (mm) sig. (0.05>P>0.025) u.s. (O.25>P>0.10) n.s. (O.10>P>0.05) sig. (0.025>P>0.01) sig. (0.05>P>0.025) u.s. (P>0.25) sig. (0.O1>P>0.005) sig. (0.025>F>.0.01) sig. (0.005>P>0.001) sig. (0.005>P>0.O01) 22.6 Peak (pg/mi) n.s. (P>O.25) 28.6 Time of peak (mm) n.s. (0.1O>P>0.05) 39.3 rea (0-480 mm) u.s. (P>0.25) 11.1 rea (0-720 mm) n.s. (P).o.25) 11.1 mount of unchanged acctaminophen excreted in urine in 24 hours (mg) N.S. (P>0.25) 24.0 * NOV=nalysis of variance for crossover design. III Summary of verage Plasma Concentrations of Nitrofurantoin in Ten Normal Subjects Following a Single 100-mg Oral Dose Time (mm) Significance verage plasma concentration level of difference C.V. (%) (pg/ml) between treatment from residual Treatment Treatment averages from NOV mean square u.s. (O.10>P>0.05) sig. (0.025>P).0.O1) n.s. (0.25>P).0.10) sig. (0.05>P>0.025) sig. (0.O1>P>0.005) u.s. (P>0.25) u.s. (P>O.25) 90.0 Peak (pg/nil) sig. (O.025>P>O.001) 31.4 rea (0-240 mm) u.s. (0.10>P>0.o5)* 48.0 * Same results obtained by paired t-test also. 266 The Journal of Clinical Pharmacology

4 IOVILJLITY OF CETM1NOPHEN ND NITROFURNTOIN TIME (MINUT.m) Fig. 1. Mean acetaminophen plasma levels for ten subjects following a single 650-my oral (lose: ( S ) treatment (soft.qelatin capsule); (,. ) treatment (commercial tablet). dosing. Urine collections were made in the following time intervals: predosc, 0-2 hours, 2-4 hours, 4-6 hours, 6-8 hours, 8-12 hours, hours. The urine samples were collected in plastic bottles without addition of any preservative. fter collection, the urine volumes were measured, the urine was quick-frozen, and kept in the frozen state until just prior to assay. modification of the analytical procedure of Conklin and Holhifields was used to assay for nitrofurantoin in plasma and urine samples. (Conklin and Hollifield employed 1 ml urine, 4 ml HO!, and 10 ml nitromethane. In the present study 2 ml urine, two drops concentrated 1101, and 4 ml nitromethane were used.) Each blood sample from both studies was drawn into one Vacutainer tube containing heparin as anticoagulant and the tubes were treated as described previously.6 The treatment schedules for both studies are outlined in Table I. Results cetaminophen. Table II summarizes average plasma concentrations and 24- hour urinary excretion data for treatments and and includes a summary of results of the analyses of variance. Figure 1 depicts graphically these average plasma levels. Inspection of the table indicates that since no significant differences in total average amounts of unchanged drug excreted in the urine and in average areas under the plasma concentration curves following the two treatments were obtained, no significant differences in bioavailability between the two treatments existed. However, Table II also shows that average plasma concentrations of acetaminophen at 10, 40, 60, 240, 360, 480, and 720 minutes differed significantly. This suggests that the rates of absorption were, on the average, significantly different following the two dosage forms. Figure 1 reveals that the peak average plasma May-June,

5 LERT ET L. concentration following treatment appeared at about 120 minutes, while that for treatment appeared at about 60 minutes; this is consistent with the hypothesis that acetaminophen in treatment (the commercial tablet) was more rapidly absorbed than acetaminophen in treatment (the soft gelatin capsule). Nitrofurantoin. Figure 2 depicts the average plasma levels obtained after oral administration of nitrofurantoin. Figure 3 summarizes the average urinary excretion data. summary from the analyses of variance appears in tabular form in Tables 111 and IV. Simlce no significant differences between mean treatment areas and in amounts of unchanged drug excreted in the urine were obtained for the two dosage forms tested, their bioavailabilities * a TIME. MINUTES Fig. 2. Mean nitrofurantoin plasma levels for ten sub jects follouiu.q a single 100-mg oral dose: ( S ) treatment (soft gelatin capsule); ( -. ) treatment (commercial tablet). were considered to be equivalent. However, the plasma level data suggest that the drug was absorbed more rapidly following administration of the soft gelatin capsule than following the commercial tablet. Table III supports this by showing that the differences between average plasma concentrations at 20, 40, and 60 minutes, as well as the difference between average peak plasma concentrations, were significant. Discussion The total amount of unchanged drug excreted in the urine and the total area under the plasma concentration curve are generally accepted as measures of relative efficiency of absorption. No significant differences were shown for either of these parameters following the two treatments in both studies. However, for nitrofurantom, the area difference gave a significance level between 0.10 and 0.05 (Table III). This fact coupled with the alternate significant-not significant pattern displayed in Table III suggests that if more subjects had been used, the plasma level nonequivalency might have been significant at all sampling times to 120 minutes as well as the area under the curve. This is supported by the large coefficients of variation calculated from the residual mean square at each sampling time, which are measures of intrasubject variation, assay error, and unknown sources of variation. The time taken for a drug to attain peak concentration is also a reflection of the rate of absorption. For acetaminophen, the difference between the mean times of individual subjects to attain peak concentration was not significant. However, as seen in Table II, the mean times of 84 and 58 minutes for treatment and, respectively, gave a significance level between 0.05 and 0.10; interpolation gave P0.07, which is a borderline level. Inspection of Fig. 1, coupled with the observation that 268 The Journal of Clinical Pharmacology

6 IOVILILITF OF CETMINOPHEN ND NITROFURNTOIN So TO Fig. 3. Mean cumulative amount (nsg) of nitrofurantoin excreted for ten subjects following a single 100-mg oral dose: ( 5 ) treatment (soft gelatin capsule); ( --U-) treatment (commercial tablet). statistically significant differences were obtained between treatment means at all sampling times after the curves intersect (about 110 minutes), is strong evidence that, indeed, the commercial tablet (treatment ) was more rapidly absorbed than the soft gelatin capsule (treatment ). For nitrofurantoin, it was difficult to assign a value for the time of maximum plasma level owing to the noncontinuous appearance of the individual subject plasma curves. Irregular concentration profiles occurred for subjects 2, 3, 4, 5, 7, 8, and 10. discrepancy appears to exist between the urinary excretion data (Table IV) Summary of the verage Cumulative mount of Nitrofurantoin Excreted by Ten Normal Subjects Following a Single 100-mg Oral Dose of Nitrofurantoin IV Cumulative amount excreted (mg) Treatment Treatment Time interval (soft gelatin (commercial (hr) capsule) tablet) Significance level of difference between treatment averages from NOV C.V. (%) from residual mean square u.s. (O.25>P>0.10) u.s. (P>0.25) ns. (P>0.25) u.s. (P>o.25) u.s. (P>o.25) u.s. (P>0.25) 24.9 May-June,

7 LERT ET L. and plasma level data (Table III) in the nitrofurantoin study. The treatment means of the cumulative amounts of nitrofurantoin excreted in the urine did not differ significantly at any time, whereas somne differences between treatnlent average plasma concentrations were significant up to 60 minutes. This type of discrepancy between urinary excretion data and plasma data is difficult to explain, but an almost identical type of disparity was reported by Langlois et al.9 in a bioavailability study of a sulfamethazole combination. plausible explanation based upon sampling times seems most reasonable. ll the statistically significant differences in average plasma level occurred in the first 60 minutes, while the first urine collection time interval was 0 to 120 minutes. pparently, urine was not collected at frequent enough time intervals to demonstrate differences that were readily delineated by plasma levels. Summ&ry In two test panels of ten subjects each, plasma levels and urinary excretion of two drugs, acetaminophen and nitrofurantoin, were measured in order to compare bioavailabilities when the drugs were formulated as commercial tablets and as specially formulated gelatin capsules. No significant differences in relative efficiency of absorption were obtained between tablets and capsules with either drug. However, when comparing rates of absorption, the soft gelatin capsule appeared slightly superior to the tablet in the nitrofurantoin study, whereas it appeared slightly inferior to the tablet in the acetaminophen study. The differences were not striking with either drug. References 1. Wagner, J. G.: iopharmaceutics and Relevant Pharmaeokinetics. Drug Intelligence Publications, Hamilton, Illinois, Gwilt, J. R., Robertson,., Goldman, L., and lauchard,. W.: The absorption characteristics of paracetamol tablets in man. J. Pharm. Pharmacol. 15:445 (1963). 3. MeGilveray, I. J., Mattok, G. L., Fooks, J. R., Jordan, N., and Cook, D.: cetaminophen. II. comparison of the physiological availabilities of different commercial dosage forms. Can. J. Pharm. Sci. 6:38 (1971). 4. Mattok, G. L., Hossie, R. D., and McGilveray, I. J.: In vivo :in vitro studies of nitrofurantoin tablets. Ibid. 7:84 (1972). 5. Horn, F. S., and Miskel, J. J.: Oral dosage form design and its influence on dissolution rates for a series of drugs. J. Pharm. Sci. 59:827 (1970). 6. Wagner, J. G., Welling, P. G., Lee, K. P., and Walker, J. E.: In rico and in vitro availability of commercial Warfarin tablets. J. Pharm. Sci. 60:666 (1971). 7. Kostenbauder, H..: tyniversity of Kentucky, Lexington, Kentucky, personal communication. 8. Conklin, J. D., and Hollifleld, H. D.: new method for the determination of nitrofurantoin in urine. Clin. Chem. 11:925 (1965). 9. Langlois, Y., Gaguon, M.., and Tetreault, L.: bioavailability study on three oral I)reparations of the combination trimethoprim-sulfamethazole. J. Clin. Pharmacol. 12:196 (1972). Please address reprint requests to: Dr. John G. Wagner, Upjohn Center for Clinical Pliarmacology, The University of Michigan, nn rbor, Mich The Journal of Clinical Pharmacology